Exogenous alpha 1-antitrypsin down-regulates SERPINA1 expression.

Autor:	Karadagi A; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Johansson H; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Zemack H; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Salipalli S; Department of Respiratory Medicine, Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Mörk LM; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Kannisto K; Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Jorns C; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Gramignoli R; Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Strom S; Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Stokkeland K; Department of Medicine, Visby Hospital, Visby, Sweden.; Department of Medicine, Gastroenterology and Hepatology Unit, Karolinska Institute, Stockholm, Sweden., Ericzon BG; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Jonigk D; Institute of Pathology, Hannover Medical School, Hannover, Germany., Janciauskiene S; Department of Respiratory Medicine, Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Nowak G; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden., Ellis ECS; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2017 May 09; Vol. 12 (5), pp. e0177279. Date of Electronic Publication: 2017 May 09 (Print Publication: 2017).
DOI:	10.1371/journal.pone.0177279
Abstrakt:	The main goal of the therapy with purified human plasma alpha1-antitrypsin (A1AT) is to increase A1AT levels and to prevent lungs from elastolytic activity in patients with PiZZ (Glu342Lys) A1AT deficiency-related emphysema. Potential hepatic gains of this therapy are unknown. Herein, we investigated the effect of A1AT therapy on SERPINA1 (gene encoding A1AT) expression. The expression of SERPINA1 was determined in A1AT or A1AT plus Oncostatin M (OSM) treated primary human hepatocytes isolated from liver tissues from A1AT deficient patients and control liver tissues. In addition, SERPINA1 mRNA was assessed in lung tissues from PiZZ emphysema patients with and without A1AT therapy, and in adherent human peripheral blood mononuclear cells (PBMC) isolated from healthy PiMM donors. In a dose-dependent manner purified A1AT lowered SERPINA1 expression in hepatocytes. This latter effect was more prominent in hepatocytes stimulated with OSM. Although it did not reach statistical significance (P = 0.0539)-analysis of lung tissues showed lower SERPINA1 expression in PiZZ emphysema patients receiving augmentation therapy relative to those without therapy. Finally, exogenously added purified A1AT (1mg/ml) reduced SERPINA1 expression in naïve as well as in lipopolysaccharide (LPS)-stimulated human adherent PBMCs. Exogenous A1AT protein reduces its own endogenous expression. Hence, augmentation with native M-A1AT protein and a parallel reduction in expression of dysfunctional mutant Z-A1AT may be beneficial for PiZZ liver, and this motivates further studies.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu PDF